tbuckley/cabot-search huggingface dataset:
Abstract 1168: From clinical mutational data to a novel lung cancer mouse model -<i>NF1</i>inactivation cooperates with<i>RASA1</i>inactivation to drive non-small cell lung cancer (NSCLC)
Authors: Lin Song, Thaidy Y. Rodriguez, Adam Olshen, Eric Collisson
Journal: Cancer Research (2022)

Abstract 11% of non-small cell lung cancer (NSCLC) patients harbor NF1 mutations. The enrichment of NF1 mutations in lung adenocarcinoma (LUAD) cases that otherwise lack activated oncogene mutations indicates that NF1 loss may play a necessary role in the activation of the RAS pathway. However, conditional, biallelic loss of Nf1 in the mouse lung is insufficient for LUAD initiation over 2 years, indicating additional genetic or epigenetic events cooperate with Nf1 loss in lung tumorigenesis. To better understand NF1 mutant lung cancers, we analyzed a lung cancer dataset with 47227 patients’ genomic mutation data from Foundation Medicine (FMI) and found that NF1 mutations (5270 patients) are associated with a higher mutational burden compared to NF1 wild type lung cancer patients in the lung cancer patients’ clinical database. We then analyzed the AACR GENIE non-small cell lung cancer datasets for genes mutated concurrently with NF1 mutation. We found that NF1 mutation statistically significantly cooccurs with RASA1 (p &amp;lt;0.001 for concurrency) and with TP53 mutations in the non-small lung cancer dataset. NF1-mutated samples lack other key driver oncogene mutations such as EGFR (p &amp;lt;0.001 for mutual exclusivity). To functionally validate our findings of genetic cooperativity, we conditionally deleted the two key GAPs: Nf1 and Rasa1 (with Trp53) in vivo. Deletion of both Nf1 and Rasa1 but neither the Nf1 or Rasa1 deletion alone lead to LUAD when combined with Trp53 deletion. Our new mouse model provides a unique tool for our ongoing effort to understand the mechanism of Nf1 &amp; Rasa1 tumor initiation in the lung and will aid preclinical investigations of targeted therapies. Citation Format: Lin Song, Thaidy Y. Rodriguez, Adam Olshen, Eric Collisson. From clinical mutational data to a novel lung cancer mouse model -NF1inactivation cooperates withRASA1inactivation to drive non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1168.
Abstract 5241: p38 MAPK/EGR1/PD-L1 axis promotes radiation resistance of nasopharyngeal carcinoma by enhancing immune evasion
Authors: Dong-Fang Meng
Journal: Cancer Research (2022)

Abstract Radiation resistance is the main reason for treatment failure. Till present, the underlying molecular mechanism of NPC radiation resistance remains poorly understood. Recent clinical trials have demonstrated that PD-1/PD-L1 inhibitors have achieved better efficacy in the treatment of recurrent or metastatic NPC. Further studies are needed to better understand the molecular mechanisms underlying PD-1/PD-L1 inhibitors enhance response to radiation in NPC. We performed RNA-seq analysis in NPC radioresistant and wild-type cells. We identified EGR1 promotes NPC radiation resistance and is significantly correlated with NPC recurrence. We further found that EGR1 upregulated PD-L1 expression at transcriptional level in a p38 MAPK dependent manner. Moreover, EGR1 participated in CD8+T cell mediated immune evasion in NPC radioresistant cells. We therefore propose a hypothesis that p38 MAPK/EGR1 axis induced PD-L1 expression promotes radiation resistance of NPC by enhancing immune evasion. This study aims to identify the key regulatory factors in p38 MAPK/EGR1/PD-L1 axis, especially PD-L1, as a new target to improve radiosensitivity of NPC, provide theoretical basis for PD-1/PD-L1 inhibitors plus radiotherapy in the treatment of NPC. Meanwhile, this study also provides the possibility for predicting the radiosensitivity of NPC. Citation Format: Dong-Fang Meng. p38 MAPK/EGR1/PD-L1 axis promotes radiation resistance of nasopharyngeal carcinoma by enhancing immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5241.
Abstract 5162: TuFEst: a sensitive and cost-effective pan-cancer detection approach with accurate tumor fraction estimation
Authors: Ziao Lin, Chip Stewart, Elizabeth E. Martin, Brian P. Danysh, Raquel A. Jacobs, Kara Slowik, Lee Lawton, Elizabeth Lightbody, Kahn Rhrissorrakrai, Filippo Utro, Chaya Levovitz, Carrie Cibulskis, Irene M. Ghobrial, Margaret Shipp, Ryan B. Corcoran, Dejan Juric, Laxmi Parida, Heather A. Parsons, Gad Getz
Journal: Cancer Research (2022)

Abstract Detecting cancer at early stages or upon recurrence is critical to decreasing cancer morbidity and mortality. We developed TuFEst (Tumor Fraction Estimator), a cost-effective computational approach for pan-cancer detection and tumor burden estimation from ultra-low coverage whole genome sequencing (~0.1x, ULP-WGS) of minimally invasive cell-free DNA (cfDNA). Current state-of-the-art methods estimate tumor fraction (TF) from ULP-WGS depending exclusively on total copy number variation, which loses tumor signal in either copy number-quiet tumors or tumors with copy-neutral loss-of-heterozygosity. Additionally, it is difficult in many cases to distinguish clonal from sub-clonal copy-number events, therefore complicating the ability to estimate tumor fraction. On the other hand, fragments shed into the blood from cancer cells, i.e., circulating tumor DNA (ctDNA), of various cancer types show significantly different length distribution than that from normal cells in healthy donors. By synergistically integrating both (i) copy number variation and (ii) altered fragment length signals, TuFEst successfully achieved higher sensitivity and more accurate TF estimation than current methods in &amp;gt;200 cfDNA samples across different cancer types, even in low tumor-fraction cases (TF &amp;lt; 0.1%). Application of TuFEst to serial cfDNA samples from blood biopsies demonstrate its utility in accurately estimating TF in ~100 cfDNAs, suggesting that TuFEst can be used to detect early cancer recurrence during different treatments. In one breast cancer patient receiving CDK4/6 therapy, TuFEst indicated disease progression 262 days earlier than routine imaging. Altogether, our work suggests that accurate TF estimation from cfDNA can not only aid in detecting cancer at early stages but also provide evidence of disease progression during treatment. We believe that such a non-invasive, cost-effective, pan-cancer detection method will benefit both initial cancer screening and monitoring of resistance to therapy in clinical applications. Citation Format: Ziao Lin, Chip Stewart, Elizabeth E. Martin, Brian P. Danysh, Raquel A. Jacobs, Kara Slowik, Lee Lawton, Elizabeth Lightbody, Kahn Rhrissorrakrai, Filippo Utro, Chaya Levovitz, Carrie Cibulskis, Irene M. Ghobrial, Margaret Shipp, Ryan B. Corcoran, Dejan Juric, Laxmi Parida, Heather A. Parsons, Gad Getz. TuFEst: a sensitive and cost-effective pan-cancer detection approach with accurate tumor fraction estimation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5162.
Abstract 5349: Single-cell analysis sheds light on the resistance mechanisms of a novel pan-HER inhibitor, pyrotinib, in non-small cell lung cancer
Authors: Xinfeng Wang, Yuan Li, Runsen Jin, Nan Sun, Jie He
Journal: Cancer Research (2022)

Abstract Recently, a novel oral, irreversible pan-HER tyrosine kinase inhibitor, pyrotinib, has shown anticancer effects on HER2-mutant non-small cell lung cancer (NSCLC) patients, but the explicit responses of lung cancer cells towards pyrotinib treatment are barely investigated. In our current study, we employed single-cell RNA sequencing to profile the longitudinal transcriptomic dynamics of lung cancer cells during the pyrotinib treatment, unraveling the potential resistance mechanisms. We treated a lung adenocarcinoma cell line, H358, with pyrotinib at doses of 100nM, 200nM, 500nM, and 1000nM every four days, respectively. Then, the untreated cells (P0) as well as longitudinal samples after each administration (P4, P8, P12, P16) were harvested for further analysis. After quality control, a total of 41,804 cells were sequenced and included for further analysis. The differentially expressed genes were determined using MAST and the differentially enriched cancer hallmark signatures based on single-sample Gene Set Variation Analysis (ssGSVA) were identified. The single-cell data revealed that the untreated cells (Sample P0) and persistent cells (Sample P16) had stable and distinct gene expression patterns, while cells during the course of treatment shared similar expression features at a transitional state. Several cancer driver genes were found to be aberrantly regulated during the administration, like EPHA2, CDKN2A, CDK4, PTEN, and MYC. Also, some pathways related to immune response were suppressed after pyrotinib treatment, including interferon alpha response, interferon gamma response, TNFA signaling via NF-κB, and inflammatory response. Intriguingly, CD274 (the gene encoding PD-L1) and LGALS9 were found to significantly decrease after pyrotinib treatment, suggesting that pyrotinib may be associated with outcomes of immunotherapy. With the large cell numbers analyzed, we distinguished an isolated, small subpopulation of cells characterized by the enriched expression of MGP, COL1A1, COL1A2, SPARC, and COL3A1 along with the elevated EMT and angiogenesis scores, suggesting its critical role in pyrotinib resistance. Collectively, our study for the first time reveals the transcriptomic evolution of NSCLC cells in response to pyrotinib administration at the single-cell resolution, providing new insights into potential mechanisms of resistance to this novel regimen in NSCLC. Citation Format: Xinfeng Wang, Yuan Li, Runsen Jin, Nan Sun, Jie He. Single-cell analysis sheds light on the resistance mechanisms of a novel pan-HER inhibitor, pyrotinib, in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5349.
Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer
Authors: Junfen Xu, Yifeng Fang, Kelie Chen, Sen Li, Sangsang Tang, Yan Ren, Yixuan Cen, Weidong Fei, Bo Zhang, Yuanming Shen, Weiguo Lu
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The heterogeneity of high-grade serous ovarian cancer (HGSOC) is not well studied, which severely hinders clinical treatment of HGSOC. Thus, it is necessary to characterize the heterogeneity of HGSOC within its tumor microenvironment (TME). Experimental Design: The tumors of 7 treatment-naïve patients with HGSOC at early or late stages and five age-matched nonmalignant ovarian samples were analyzed by deep single-cell RNA sequencing (scRNA-seq). Results: A total of 59,324 single cells obtained from HGSOC and nonmalignant ovarian tissues were sequenced by scRNA-seq. Among those cells, tumor cells were characterized by a set of epithelial-to-mesenchymal transition (EMT)-associated gene signatures, in which a combination of NOTCH1, SNAI2, TGFBR1, and WNT11 was further selected as a genetic panel to predict the poor outcomes of patients with HGSOC. Matrix cancer-associated fibroblasts (mCAF) expressing α-SMA, vimentin, COL3A, COL10A, and MMP11 were the dominant CAFs in HGSOC tumors and could induce EMT properties of ovarian cancer cells in the coculture system. Specific immune cell subsets such as C7-APOBEC3A M1 macrophages, CD8+ TRM, and TEX cells were preferentially enriched in early-stage tumors. In addition, an immune coinhibitory receptor TIGIT was highly expressed on CD8+ TEX cells and TIGIT blockade could significantly reduce ovarian cancer tumor growth in mouse models. Conclusions: Our transcriptomic results analyzed by scRNA-seq delineate an ecosystemic landscape of HGSOC at early or late stages with a focus on its heterogeneity with TME. The major applications of our findings are a four–EMT gene model for prediction of HGSOC patient outcomes, mCAFs’ capability of enhancing ovarian cancer cell invasion and potential therapeutic value of anti-TIGIT treatment.
Abstract 459: Identification of the PDAC immunogenic subtype using deep learning with multi-scaled digital H&amp;E images
Authors: Han Si, Steven Xu, Anantharaman Muthuswamy, Ryan Liang, Kate Sasser, Hisham K. Hamadeh, Suzana Couto, Brandon Higgs
Journal: Cancer Research (2022)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has proven a difficult cancer to treat. To improve treatment strategies, molecular subtypes have been identified, one being immunogenic with significant immune infiltrate and better prognosis. These subtypes have been determined by RNA profiling, which often exhibits technical challenges in a clinical setting. Here we present a deep learning-based method to identify PDAC immunogenic patients using H&amp;E images. This method is robust to RNA quality issues and can elucidate unique morphological features not obtainable with RNA profiling to refine the selection of patients with this phenotype. Methods: Patients (n=265) were primarily stage II or IV, treated previously with gemcitabine+nab-paclitaxel or FOLFIRINOX. Ground truth for immunogenic subtype (n=105) was defined with RNASeq. Whole slide images were subdivided into non-overlapping, fixed-size tiles at 4 magnifications: 2.5x, 5x, 10x, 20x, followed by feature extraction using a ResNet50 convolutional neural network. Principal component (PC) analysis reduced dimensionality of extracted features in each tile. The dataset was split into 80% training, 20% testing. Posterior probabilities from a linear model were inputs to a support vector machine to predict outcome (2-step model). Progression- free survival (PFS) was evaluated using the Kaplan Meier method. Results: ImageNet-trained ResNet50 model extracted 2048 features from each tile and the first 75 PCs, explaining 87% variance, were input into the 2-step model; average AUC=0.77 (95% CI=0.70,0.83) across the 4 magnification datasets. A multi-scale ensemble approach combining these 4 magnifications improved the AUC to 0.80 (95% CI=0.66,0.93). Accuracy, sensitivity, and specificity were 0.79, 0.76, and 0.81, respectively. The predicted immunogenic subtype showed significantly improved PFS compared to the other 3 subtypes (HR 95%CI = 0.54 (0.36,0.81), p=0.003), while the RNASeq-derived immunogenic subtype had less differentiation (HR 95%CI = 0.64 (0.42,0.98), p=0.04). Conclusions: This study presents a deep learning 2-step model approach using tumor H&amp;E images to identify PDAC immunogenic subtype, with improved prognostic potential to that identified by RNA profiling, suggesting possible application in clinical settings for patient stratification. Future work will expand the model to larger independent cohorts. Citation Format: Han Si, Steven Xu, Anantharaman Muthuswamy, Ryan Liang, Kate Sasser, Hisham K. Hamadeh, Suzana Couto, Brandon Higgs. Identification of the PDAC immunogenic subtype using deep learning with multi-scaled digital H&amp;E images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 459.
Race-Free Estimation of Kidney Function
Authors: L. Ebony Boulware, Dinushika Mohottige, Matthew L. Maciejewski
Journal: JAMA (2022)

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Abstract 3618: Loss of SETD2 sensitizes kidney cancer cells to DNA methylation inhibitors by inducing viral mimicry and RNA mis-splicing
Authors: Hong-Tao Li, Hyo Sik Jang, Krizia Rohena-Rivera, Hemant Gujar, Minmin Liu, Justin Kulchycki, Xinyi Zhou, Shuqing Zhao, Peter Jones, Neil Bhowmick, Gangning Liang
Journal: Cancer Research (2022)

Abstract Large-scale sequencing efforts of human cancers have identified recurrent mutations and deletions in a variety of chromatin-regulating proteins that modulate DNA methylation, histone modifications, and nucleosome positioning. The dysregulation of histone H3 lysine 36 (H3K36) methyltransferase, SETD2, through transcriptional or genetic aberrations is associated with worse clinical outcomes and metastasis in kidney cancer. Limited targeted therapeutic interventions are available for aggressive SETD2-mutant ccRCC tumors. Here, we reveal that kidney cancer cells displaying diminished H3K36 trimethylation levels, a consequence of SETD2 deficiency, show increased sensitivity of anti-tumor effects to DNA hypomethylating agent (HMA). We discovered that HMA treatment induced stronger viral mimicry activation and immune upregulation, which is potentiated by higher transposable element (TE) expression in SETD2-mutant cancer cells. Mechanistically, we provide evidence that substantial number of the HMA-induced TE expression is a consequence of mis-splicing, which is associated deficient in slicing in SETD2-loss content along with rapid gain of H3K9me3 across exons. These all suggested HMA could turn immune-cold tumor to immune-hot tumor and sensitize tumors to immune therapy. Then we performed in vivo assay in immune competent mice. Indeed, SETD2 deficient tumors were extremely sensitive to combination treatment of HMA and immune checkpoint inhibitor. Our finding provides one of the first preclinical and in vivo evidence that demonstrates the SETD2 dysregulation can be an epigenetic therapeutic target in ccRCC, especially in combination with immune checkpoint inhibitors, for future clinical trials. Citation Format: Hong-Tao Li, Hyo Sik Jang, Krizia Rohena-Rivera, Hemant Gujar, Minmin Liu, Justin Kulchycki, Xinyi Zhou, Shuqing Zhao, Peter Jones, Neil Bhowmick, Gangning Liang. Loss of SETD2 sensitizes kidney cancer cells to DNA methylation inhibitors by inducing viral mimicry and RNA mis-splicing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3618.
Abstract 1640: Enhanced development of functional human innate immune cells in a novel FLT3nullNSG mouse strain expressing human FLT3L
Authors: Li-Chin Yao, Shantashri Vaidya, Pali Kaur, James G. Keck, Leonard D. Shultz, Dale L. Greiner, MIchael A. Brehm
Journal: Cancer Research (2022)

Abstract Humanized mice are being applied widely to study human immune system homeostasis, function, and as a testing platform for cancer immunotherapies. A major limitation for many humanized mouse models is the lack of functional and mature human innate immune cells, which are critical for effective human immune system-tumor interactions. Previous studies have demonstrated that delivery of human FLT3L into immunodeficient mice that lack mouse FLT3, promotes the development of human innate immune cell subsets following engraftment with human hematopoietic stem cells (HSC). Here we describe a NOD-scid IL2rgnull (NSG) mouse that lacks the expression of mouse FLT3 and expresses human FLT3L transgenically (NSG-mFLT3nullTg (HuFLT3L) or NSG-FLT3L. In these studies, NSG-FLT3L and NSG mice were engrafted with human umbilical cord blood (UCB) CD34+ HSC and compared for human immune system development and function. HSC-engrafted NSG-FLT3L and NSG mice show similar levels of total human CD45+ cells in blood over the course of 18 weeks post-engraftment. However, HSC-engrafted NSG-FLT3L mice show significantly higher levels of human CD141+ and CD1c+ DC subsets, CD123+ pDC, CD14+ monocytes, CD56+ NK cells and CD3+ T cells in the blood as compared to NSG mice. CD34-FLT3L mice also show increased levels of human immune cell infiltration into the gut mucosa. CD56+ NK cells and CD3+ T cells from HSC-engrafted NSG-FLT3L mice express granzyme A and granzyme B, indicating cytotoxic activity. Following treatment of HSC-engrafted NSG-FLT3L mice with LPS, heightened levels of human cytokines were detected in serum samples, confirming innate immune system function. The growth kinetics of tumor cells from a triple negative breast cancer cell line MDA-MB-231 and a lung PDX model LG1306 in HSC-engrafted NSG-FLT3L mice are work in progress and will be compared with HSG-engrafted NSG mice. Overall these results demonstrate that the NSG-FLT3L model supports enhanced development of functional, human innate immune cells and is a novel tool to study human immuno-oncology. Citation Format: Li-Chin Yao, Shantashri Vaidya, Pali Kaur, James G. Keck, Leonard D. Shultz, Dale L. Greiner, MIchael A. Brehm. Enhanced development of functional human innate immune cells in a novel FLT3nullNSG mouse strain expressing human FLT3L [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1640.